Antibiotics may increase susceptibility to mucosal herpes infection
Protective mechanisms of commensal bacteria against viral infection are limited to how immune inductive signals are provided by commensal bacteria for enhancing immunity. Whether, or how, commensal bacteria might influence the effector arm of immune responses remains unknown. Here, we demonstrate that dysbiosis within the vaginal microbiota results in severe impairment of antiviral protection against HSV-2 infection. IL-33 released into the vaginal tract after antibiotic treatment blocks the ability of effector T cells to migrate into the vaginal tissue and secrete the antiviral cytokine, IFN-γ. Thus, our findings suggest a previously unstudied role of commensal bacteria in the effector phase of the antiviral immune response against genital herpes.
Commensal bacteria support various immunologic functions, including the development of lymphoid tissues and maintenance of intestinal immune homeostasis through regulation of Treg and Th17 differentiation. Recently, the roles of intestinal commensal bacteria in immune protection against infection by viruses such as mucosal influenza virus and systemic LCMV have been reported. Moreover, the compartmentalized control of skin immunity by resident commensal bacteria has been investigated; however, the mechanisms revealed by these studies are limited to how immune inductive signals are provided by commensal bacteria for enhancing immunity. However, whether, or how, commensal bacteria might influence the effector arm of immune responses is unknown. Moreover, almost nothing is known about the role of microbiota in immune responses within the female reproductive tract. For these reasons, we sought to investigate a previously unstudied role of commensal bacteria in the effector phase of the antiviral immune response using a physiologically relevant model of genital herpes in mice.
Our study revealed that the depletion of commensal bacteria by oral antibiotics induces the outgrowth of pathogenic bacteria in the vagina. We found that following dysbiosis caused by oral antibiotic treatment, IL-33, an alarmin released from damaged cells, is robustly secreted by the vaginal epithelia. We show that this cytokine suppresses antiviral immunity against mucosal HSV-2 infection by rendering the effector T cells incapable of secreting the key antiviral cytokine, IFN-γ within the vaginal tissue.
Notably, antibiotic treatment did not affect the ability of the animals to induce primary immune responses in the draining lymph nodes, but rather, specifically affected the ability of effector T cells to migrate into the vaginal tissue and secrete IFN-γ. Taken together, our study reveals unique insight into the role of commensal bacteria in maintaining the integrity of the surface barrier epithelial cells by preventing pathogenic bacteria colonization, thereby supporting a microenvironment conducive to antiviral defense.
The influence of microbiota on viral infections could be either protective or detrimental for the host. Here, we found that dysbiosis caused by oral antibiotic treatment impairs antiviral immunity following vaginal mucosal viral infection through the release of IL-33, an alarmin released in response to tissue damage. These findings provide insight into the mechanisms of homeostasis maintained by commensal bacteria, and reveal a deleterious consequence of dysbiosis in antiviral immune defense. These results also prompt clinically relevant questions regarding the use of oral antibiotics in susceptibility to various sexually transmitted viruses. We believe that this study will catalyze further investigations into the role of vaginal microbiota in health and disease.
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